Novel hexafluoroisopropanol derivatives

ABSTRACT

The invention is concerned with novel hexafluoroisopropanol derivatives of formula (I)  
                 
 
wherein R 1  to R 6 , m and n are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds bind to LXR alpha and LXR beta and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/168,622,filed Jun. 27, 2005, now pending. The entire contents of theabove-identified application is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention is directed to novel hexafluoroisopropanol derivatives ofthe formula (I):

Further, the invention is concerned with a process for the manufactureof the above compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Liver-X-Receptors (LXRs) are members of the nuclear hormone receptorsuperfamily. The LXRs are activated by endogenous oxysterols andregulate the transcription of genes controlling multiple metabolicpathways. Two subtypes, LXRalpha and LXRbeta, have been described (Willyet al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sci USA.1994, 91:10809-13). LXRbeta is ubiquitously expressed, while LXRalpha ispredominantly expressed in cholesterol metabolizing tissues such as theliver, adipose, intestine and macrophage. The LXRs modulate a variety ofphysiological responses including regulation of cholesterol absorption,cholesterol elimination (bile acid synthesis), and transport ofcholesterol from peripheral tissues via plasma lipoproteins to theliver. The LXRs are also involved in glucose metabolism, cholesterolmetabolism in the brain, cell differentiation, and inflammation.

At present, approximately half of all patients with coronary arterydisease have low concentrations of plasma high-density lipoproteincholesterol (HDL-C). The atheroprotective function of HDL was firsthighlighted almost 25 years ago and stimulated exploration of thegenetic and environmental factors that influence HDL-C levels (Miller NE., Lipids 1978, 13:914-9). The protective function of HDL derives fromits role in a process termed reverse cholesterol transport. HDL mediatesthe removal of cholesterol from cells in peripheral tissues, includingmacrophage foam cells in the atherosclerotic lesions of the arterialwall. HDL delivers its cholesterol to the liver and sterol-metabolizingorgans for conversion to bile and elimination in feces. Studies haveshown that HDL-C levels are predictive of coronary artery disease riskindependently of low-density lipoprotein cholesterol (LDL-C) levels(Gordon et al., Am J. Med. 1977, 62:707-14).

At present, the estimated age-adjusted prevalence among Americans age 20and older who have HDL-C of less than 35 mg/dl is 16% (males) and 5.7%(females). A substantial increase of HDL-C is currently achieved bytreatment with niacin in various formulations. However, the substantialunfavorable side-effects limit the therapeutic potential of thisapproach.

It has been observed that as many as 90% of the 14 million diagnosedtype 2 diabetic patients in the United States are overweight or obese,and a high proportion of type 2 diabetic patients have abnormalconcentrations of lipoproteins. Studies have shown that the prevalenceof total cholesterol >240 mg/dl is 37% in diabetic men and 44% in women.The rates for LDL-C >160 mg/dl are 31% and 44%, and for HDL-C<35 mg/dlare 28% and 11%, in diabetic men and women respectively. Diabetes is adisease in which a patient's ability to control glucose levels in bloodis decreased because of partial impairment in response to the action ofinsulin. Type II diabetes (T2D) is also called non-insulin dependentdiabetes mellitus (NIDDM) and has been shown to afflict 80-90% of alldiabetic patients in developed countries. In T2D, the pancreatic Isletsof Langerhans continue to produce insulin. However, the target organsfor insulin action, mainly muscle, liver and adipose tissue, exhibit aprofound resistance to insulin stimulation. The body continues tocompensate by producing unphysiologically high levels of insulin, whichultimately decreases in the later stages of the disease, due toexhaustion and failure of pancreatic insulin-producing capacity. Thus,T2D is a cardiovascular-metabolic syndrome associated with multipleco-morbidities, including insulin resistance, dyslipidemia,hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The first line of treatment for dyslipidemia and diabetes at presentgenerally involves a low-fat and low-glucose diet, exercise and weightloss. However, compliance can be moderate, and as the diseaseprogresses, treatment of the various metabolic deficiencies becomesnecessary with lipid-modulating agents such as statins and fibrates fordyslipidemia, and hypoglycemic drugs, e.g. sulfonylureas, metformin, orinsulin sensitizers of the thiazolidinedione (TZD) class ofPPARγ-agonists, for insulin resistance. Recent studies provide evidencethat modulators of LXRs would result in compounds with enhancedtherapeutic potential, and as such, modulators of LXRs should improvethe plasma lipid profile, and raise HDL-C levels (Lund et al.,Arterioscler. Thromb. Vasc. Biol. 2003, 23:1169-77). LXRs are also knownto control the efflux of cholesterol from the macrophage foam cell ofthe atherosclerotic lesion, and agonists of LXRs have been shown to beatheroprotective (Joseph and Tontonoz, Curr. Opin. Pharmacol. 2003,3:192-7). Thus, modulators of LXRs would be effective treatments for theatherosclerotic disease which underlies the cardiovascular morbidity andmortality of stroke and heart disease. Recent observations also suggestthat there is an independent LXR mediated effect oninsulin-sensitization in addition to its role in atheroprotection (Caoet al., J Biol Chem. 2003, 278:1131-6). Thus LXR modulators can alsoshow superior therapeutic efficacy on HDL-raising and atheroprotection,with additional effects on diabetes, compared to current therapies.

The novel compounds of the present invention have been found to bind toand selectively activate LXR alpha and LXR beta or coactivate LXR alphaand LXR beta. Consequently, cholesterol absorption is reduced, HDLcholesterol is increased, and inflammatory atherosclerosis is reduced.Since multiple facets of combined dyslipidemia and cholesterolhomeostasis are addressed by LXR modulators, novel compounds of thepresent invention have an enhanced therapeutic potential compared to thecompounds already known in the art. They can therefore be used in thetreatment and prophylaxis of diseases which are modulated by LXR alphaand/or LXR beta agonists. Such diseases include increased lipid andcholesterol levels, particularly low HDL-cholesterol, highLDL-cholesterol, atherosclerotic diseases, diabetes, particularlynon-insulin dependent diabetes mellitus, metabolic syndrome,dyslipidemia, Alzheimer's disease, sepsis, and inflammatory diseasessuch as colitis, pancreatitis, cholestasis/fibrosis of the liver,psoriasis and other inflammatory diseases of the skin, and diseases thathave an inflammatory component such as Alzheimer's disease orimpaired/improvable cognitive function. Moreover, the novel compounds ofthe present invention can be used for treatment and prophylaxis ofage-related and inherited (e.g. Stargardt's disease) forms of maculardegeneration.

Other compounds that bind to and activate LXR alpha and LXR beta havepreviously been suggested (e.g.: WO 03/099769). However, there is stilla need for new compounds with improved properties. The present inventionprovides the novel compounds of formula (I) which bind to LXR alphaand/or LXR beta. The compounds of the present invention unexpectedlyexhibit improved pharmacological properties compared to the compoundsknown in the art, concerning e.g. metabolic stability, bioavailabilityand activity.

SUMMARY OF THE INVENTION

In an embodiment of the invention, provided is a compound of formula(I):

whereinR¹ is hydrogen, halogen, or lower-alkyl;R² is lower-alkyl, fluoro-lower-alkyl, cycloalkyl-lower-alkyl, orheterocyclyl-lower-alkyl;R³ is hydrogen, lower-alkyl, aryl, cycloalkyl, or heterocyclyl;R⁴ is hydrogen, hydroxy, lower-alkoxy, aryl-lower-alkoxy, orheterocyclyl-lower-alkoxy;R⁵ is hydrogen, lower-alkyl, aryl, or heterocyclyl;R⁶ is aryl, heterocyclyl, or

R⁷ is lower-alkyl or fluoro-lower-alkyl;R⁸ is phenyl which is optionally substituted with 1 to 3 substituentsselected from the group consisting of hydroxy, amino, halogen,lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R⁹—O—C(O)—,R¹⁰R¹¹NC(O)—, R¹²—O—C(O)-lower-alkyl, R¹³—O—C(O)-hydroxy-lower-alkyl,R¹⁴R¹⁵NC(O)-lower-alkyl, R¹⁶R¹⁷NC(O)-hydroxy-lower-alkyl, lower-alkoxy,aryl-lower-alkoxy, R¹⁸—O—C(O)-lower-alkoxy andR¹⁹R²⁰NC(O)-lower-alkyoxy;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰independently from each other are hydrogen or lower-alkyl;L is a single bond, lower-alkylene, or lower-alkenylene;m is 0 to 3;n is 0 or 1;and pharmaceutically acceptable salts and esters thereof.

In another embodiment of the present invention, a process for themanufacture of compounds of formula (I) as defined above is provided,the process comprising the steps of:

a) reacting a compound of formula (II)

with a compound LG-CHR³—(CH₂)_(m)—(CR⁴R⁵)_(n)—R⁶, orb) reacting a compound of formula (III)

with a compound LG-R²,wherein R¹, R², R³, R⁴, R⁵, R⁶, m and n are as defined in any of claims1-23 and LG is a leaving group.

In a further embodiment of the present invention, provided is apharmaceutical composition comprising a therapeutically effective amountof a compound of the formula I as defined above and a pharmaceuticallyacceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, a method isprovided for the therapeutic and/or prophylactic treatment of diseaseswhich are modulated by LXR alpha and/or LXR beta agonists, comprisingthe step of administering a therapeutically effective amount of acompound of the formula I as defined above to a patient in need thereof.

DETAILED DESCRIPTION

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. Lower-alkyl groups asdescribed below also are preferred alkyl groups.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like. Lower-alkyl groupscan optionally be substituted, e.g. by hydroxy. Such substitutedlower-alkyl-groups are referred to as “hydroxy-lower-alkyl”. Otherpossible optional substituents are e.g. halogen. Unsubstitutedlower-alkyl groups are preferred.

The term “fluoro-lower-alkyl” refers to lower-alkyl groups which aremono- or multiply substituted with fluorine. Examples offluoro-lower-alkyl groups are e.g. CFH₂, CF₂H, CF₃, CF₃CH₂, CF₃(CH₂)₂,(CF₃)₂CH and CF₂H—CF₂. The term “cycloalkyl” refers to a monovalentcarbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl.

The term “thio-alkoxy” refers to the group R′—S—, wherein R′ is analkyl. The term “thio-lower-alkoxy” refers to the group R′—S—, whereinR′ is a lower-alkyl.

The term “fluoro-lower-alkoxy” refers to the group R″—O—, wherein R″ isfluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g.CFH₂—O, CF₂H—O, CF₃—O, CF₃CH₂—O, CF₃(CH₂)₂—O, (CF₃)₂CH—O, andCF₂H—CF₂—O.

The term “alkenyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising anolefinic bond and 2 to 20, preferably 2 to 16 carbon atoms, morepreferably 2 to 10 carbon atoms. Lower-alkenyl groups as described belowalso are preferred alkenyl groups. The term “lower-alkenyl” refers to astraight-chain or branched hydrocarbon residue comprising an olefinicbond and 2 to 7, preferably 2 to 4 carbon atoms, such as e.g.2-propenyl.

The term “alkynyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising a triplebond and up to 20, preferably up to 16 carbon atoms. The term“lower-alkynyl” refers to a straight-chain or branched hydrocarbonresidue comprising a triple bond and 2 to 7, preferably 2 to 4 carbonatoms, such as e.g. 2-propynyl. Lower-alkynyl groups can be substituted,e.g. by hydroxy.

The term “alkylene” refers to a straight chain or branched divalentsaturated aliphatic hydrocarbon group of 1 to 20 carbon atoms,preferably 1 to 16 carbon atoms, more preferably up to 10 carbon atoms.Lower-alkylene groups as described below also are preferred alkylenegroups.

The term “lower-alkylene” refers to a straight chain or brancheddivalent saturated aliphatic hydrocarbon group of 1 to 7, preferably 1to 6 or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylenegroups are preferred.

The term “alkenylene” refers to a straight chain or branched divalenthydrocarbon group comprising an olefinic bond and up to 20 carbon atoms,preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms.Lower-alkenylene groups as described below also are preferred alkenylenegroups. The term “lower-alkenylene” refers to a straight chain orbranched divalent hydrocarbon group comprising an olefinic bond and upto 7, preferably up to 5, C-atoms. Straight chain alkenylene orlower-alkenylene groups are preferred.

The term “aryl” relates to the phenyl or naphthyl group, preferably thephenyl group, which can optionally be substituted by 1 to 5, preferably1 to 3, substituents independently selected from the group consisting oflower-alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forminge.g. a benzodioxyl group), halogen, hydroxy, CN, CF₃, NH₂, N(H,lower-alkyl), N(lower-alkyl)₂, aminocarbonyl, carboxy, NO₂,lower-alkoxy, thio-lower-alkoxy, lower-alkylsulfonyl, aminosulfonyl,lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl,lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy,lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy,carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, NH₂-lower-alkoxy, N(H,lower-alkyl)-lower-alkoxy, N(lower-alkyl)₂-lower-alkoxy, andbenzyloxy-lower-alkoxy. Preferred substituents are halogen andfluoro-lower-alkyl.

The term “heterocyclyl”, alone or in combination, signifies a saturated,partially unsaturated or aromatic 5- to 10-membered, mono- or bicyclicheterocycle which contains one or more hetero atoms selected fromnitrogen, oxygen and sulphur. If desired, it can be substituted on oneor more carbon atoms e.g. by halogen, alkyl, alkoxy, oxo etc. and/or ona secondary nitrogen atom (i.e. —NH—) by alkyl, cycloalkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. ═N—) by oxido, with halogen, alkyl, cycloalkyl andalkoxy being preferred. Examples of such heterocyclyl groups arepyrrolidinyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, pyrazoyl, triazolyl, tetrazolyl, isothiazolyl,imidazoyl (e.g. imidazol-4-yl and 1-benzyloxycarbonyl-imidazol-4-yl),benzoimidazolyl, pyrazoyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, indolyl (e.g. 2-indolyl), indazolyl, quinolyl (e.g.2-quinolyl, 3-quinolyl and 1-oxido-2-quinolyl), isoquinolyl (e.g.1-isoquinolyl and 3-isoquinolyl), tetrahydroquinolyl (e.g.1,2,3,4-tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (e.g.1,2,3,4-tetrahydro-1-oxo-isoquinolyl), tetrahydropyranyl, quinoxalinyl,oxopyrrolidinyl and benzo[b]thiophenyl. Preferred are pyridinyl,thiazolyl and benzo[b]thiophenyl. A heterocyclyl group may also have asubstitution pattern as described earlier in connection with the term“aryl”. Aromatic heterocyclyl groups are preferred.

The term “leaving group” refers to a group that may be displaced by anucleophile (e.g. a secondary amine). Typical leaving groups are e.g.:Cl, Br, I, O—SO₂-lower-alkyl (wherein O—SO₂—CH₃=OMs),O—SO₂-lower-fluoroalkyl (wherein O—SO₂—CF₃=OTf), O—SO₂-aryl (whereinwherein O—SO₂-ptolyl=OTs), O-(para-nitrophenyl).

Compounds of formula (I) can form pharmaceutically acceptable acidaddition salts. Examples of such pharmaceutically acceptable salts aresalts of compounds of formula (I) with physiologically compatiblemineral acids, such as hydrochloric acid, sulphuric acid, sulphurousacid or phosphoric acid; or with organic acids, such as methanesulphonicacid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroaceticacid, citric acid, fumaric acid, maleic acid, tartaric acid, succinicacid or salicylic acid. The term “pharmaceutically acceptable salts”refers to such salts. Compounds of formula (I) in which a COOH group ispresent can further form salts with bases. Examples of such salts arealkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca—and Trimethylammoniumsalt. The term “pharmaceutically acceptable salts”also refers to such salts. Salts obtained by the addition of an acid arepreferred.

The term “pharmaceutically acceptable esters” embraces derivatives ofthe compounds of formula (I), in which a carboxy group has beenconverted to an ester. Lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- ordi-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,pyrrolidino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl,lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples ofsuitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arepreferred esters. The methyl and ethyl esters are especially preferred.The term “pharmaceutically acceptable esters” furthermore embracescompounds of formula (I) in which hydroxy groups have been converted tothe corresponding esters with inorganic or organic acids such as, nitricacid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

In detail, the present invention relates to compounds of formula (I)

whereinR¹ is hydrogen, halogen, or lower-alkyl;R² is lower-alkyl, fluoro-lower-alkyl, cycloalkyl-lower-alkyl, orheterocyclyl-lower-alkyl;R³ is hydrogen, lower-alkyl, cycloalkyl, aryl, or heterocyclyl;R⁴ is hydrogen, hydroxy, lower-alkoxy, aryl-lower-alkoxy, orheterocyclyl-lower-alkoxy;R⁵ is hydrogen, lower-alkyl, aryl, or heterocyclyl;R⁶ is aryl, heterocyclyl, or

R⁷ is lower-alkyl or fluoro-lower-alkyl;R⁸ is phenyl which is optionally substituted with 1 to 3 substituentsselected from the group consisting of hydroxy, amino, halogen,lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R⁹—O—C(O)—,R¹⁰R¹¹NC(O)—, R¹²—O—C(O)-lower-alkyl, R¹³—O—C(O)-hydroxy-lower-alkyl,R¹⁴R¹⁵NC(O)-lower-alkyl, R¹⁶R¹⁷NC(O)-hydroxy-lower-alkyl, lower-alkoxy,aryl-lower-alkoxy, R¹⁸—O—C(O)-lower-alkoxy andR¹⁹R²⁰NC(O)-lower-alkyoxy;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰independently from each other are hydrogen or lower-alkyl;L is a single bond, lower-alkylene or lower-alkenylene;m is 0 to 3;n is 0 or 1;and pharmaceutically acceptable salts and esters thereof.

Compounds of formula (I) are individually preferred and physiologicallyacceptable salts thereof are individually preferred and pharmaceuticallyacceptable esters thereof are individually preferred, with the compoundsof formula (I) being particularly preferred.

The compounds of formula (I) can have one or more asymmetric C atoms andcan therefore exist as an enantiomeric mixture, diastereomeric mixtureor as optically pure compounds.

Preferred compounds of formula (I) as described above are those, whereinR¹ is hydrogen or halogen, preferably hydrogen or chlorine. Hydrogen andchlorine individually constitute preferred embodiments. Other preferredcompounds of formula (I) as described above are those, wherein R² islower-alkyl or fluoro-lower-alkyl, particularly ethyl or2,2,2-trifluoro-ethyl. Ethyl and 2,2,2-trifluoroethyl individuallyconstitute preferred embodiments.

Another preferred embodiment of the present invention relates tocompounds of formula (I) as described above, wherein R³ is hydrogen oraryl, particularly hydrogen or phenyl, especially hydrogen.

Other preferred compounds of formula (I) as described above are those,wherein R⁴ is hydrogen or hydroxy. Compounds wherein R⁵ is hydrogen arealso preferred.

A further preferred embodiment of the present invention relates tocompounds of formula (I) as described above, wherein R⁶ is phenyl,pyridinyl, thiazolyl, or benzo[b]thiophenyl, which is optionallysubstituted with halogen. Each of the these groups can optionally besubstituted with halogen, preferably phenyl or benzo[b]thiophenyl.Preferably, R⁶ is phenyl, chloro-phenyl, pyridinyl, thiazolyl, orchloro-benzo[b]thiophenyl, more preferably phenyl.

Another preferred embodiment of the present invention relates tocompounds as described above, wherein R⁶ is

wherein R⁷ is lower-alkyl; R⁸ is phenyl which is optionally substitutedwith a substituent selected from the group consisting of halogen,fluoro-lower-alkyl, R⁹—O—C(O)—, R¹⁰R¹¹NC(O)— and aryl-lower-alkoxy; R⁹is hydrogen or lower-alkyl; R¹⁰ and R¹¹, independently from each otherare hydrogen or lower-alkyl; L is a single bond, lower-alkylene, orlower-alkenylene. In such compounds, R⁷ preferably is methyl. R⁸preferably is phenyl substituted with fluoro-lower-alkyl, halogen,carboxy, or (lower-alkyl)₂NC(O)—. More preferably, R⁸ is3-trifluoromethyl-phenyl, 3-chloro-phenyl, 4-carboxy-phenyl, or4-(CH₃)₂NC(O)-phenyl. Furthermore, L preferably is a single bond.

In a preferred embodiment of the present invention, m is 0 to 2, morepreferably m is 0. Compounds of formula (I) as described above, whereinn is 0 also constitute a preferred embodiment of the present invention.

In particular, preferred compounds are the compounds of formula (I)described in the examples as individual compounds as well aspharmaceutically acceptable salts as well as pharmaceutically acceptableesters thereof.

Preferred compounds of formula (I) are those selected from the groupconsisting of

-   2-[4-(Benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[(2-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[(3-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[(4-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-[4-(Ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-[4-(Benzhydryl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[ethyl-(pyridin-2-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[ethyl-(pyridin-3-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[ethyl-(pyridin-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[(5-Chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   (R)    2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   (S)    2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   (R)    2-(4-{[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-[4-(Benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{3-Chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-[3-Chloro-4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   1,1,1,3,3,3-Hexafluoro-2-{4-[[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-propan-2-ol,-   2-{4-[[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{Ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(3-Chloro-4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(3-Chloro-4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{[2-(3-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic    acid methyl ester,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic    acid methyl ester,-   3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic    acid,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic    acid,-   3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide,-   3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide,-   3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide,-   2-{4-[(2-Benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{Ethyl-[5-methyl-2-((E)-styryl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,    and-   2-{4-[ethyl-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,    and pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds of formula (I) are those selected fromthe group consisting of

-   2-[4-(Benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{Ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   2-(4-{[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic    acid, and-   4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide,    and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that the compounds of general formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

The invention further relates to a process for the manufacture ofcompounds of formula (I) as defined above, which process comprisesa) reacting a compound of formula (II)

with a compound LG-CHR³—(CH₂)_(m)—(CR⁴R⁵)_(n)—R⁶, orb) reacting a compound of formula (III)

with a compound LG-R²,wherein R¹, R², R³, R⁴, R⁵, R⁶, m and n are as defined above and LG is aleaving group.

The reaction of a compound of formula (II) with a compoundLG-CHR³—(CH₂)_(m)—(CR⁴R⁵)_(n)—R⁶ or of a compound of formula (III) witha compound LG-R can be performed under reaction conditions well known tothe person skilled in the art. Such reactions can conveniently becarried out in a solvent such as e.g. DMF, THF, acetonitrile or acetone,optionally in the presence of a base such as e.g. DIPEA or K₂CO₃, at asuitable temperature, e.g. in the range of 20-200° C. Suitable leavinggroups are well known in the art, e.g. halogenide (I, Br, Cl), triflate(OTf), mesylate (OMs), tosylate (OTs), or para-nitrophenolate.

The present invention also relates to compounds of formula (I) asdefined above, when prepared by a process as described above.

The preparation of compounds of formula (I) as defined above, isillustrated in scheme 1.

Treatment of an aniline 1a/b (PG=optional protective group) with LG-R²(wherein LG is a leaving group such as e.g. Cl, Br, I, MsO, TsO, or TfO)or with an acylating agent (a carboxylic acid anhydride or carboxylicacid chloride such as e.g. trifluoroacetic acid anhydride or benzoylchloride) and subsequent reduction of the intermediate amide (e.g. withBH₃) leads to 2a/b (step a). Alternatively the formation of theintermediate amide may also be carried out by treatment of 1a/b with acarboxylic acid in presence of e.g. EDCI and HOBT or other typicalreagents used for the formation of amides from carboxylic acids. The“(CHR³)(CH₂)_(m)(CR⁴R⁵)_(n)R⁶”-moiety is introduced in step b byreaction of 2a/b with a compound “LG-(CHR³)(CH₂)_(m)(CR⁴R⁵)_(n)R⁶”.Alternatively, 2a/b can be treated with an acylating agent such asClOC(CH₂)_(m)(CR⁴R⁵)_(n)R⁶ in presence of a base or with a carboxylicacid HOOC(CH₂)_(m)(CR⁴R⁵)_(n)R⁶ in the presence of e.g. EDCI and HOBT orother typical reagents used for the formation of amides from carboxylicacids. The resulting amide intermediate is reduced (e.g. with BH₃) togive derivatives with R³=H. If 2a/b is treated with oxirane 5,optionally in the presence of a Lewis acid such as e.g.lithiumperchlorate or ZnCl₂ (in analogy to e.g.: Chini et al., J. Org.Chem., 1991, 56(20) 5939-5942; Duran Pachon et al., Tet. Lett., 2003,44(32) 6025-6027), derivatives with m=0, n=1 and R⁵=OH can be obtained.The methods used for the introduction of the“(CHR³)(CH₂)_(m)(CR⁴R⁵)_(n)R⁶”-moiety can also be applied to 1a/b (stepc). The R²-substituent is introduced subsequently into 4a/b according tothe methods described above (step d). If step d is incompatible withfunctional groups present in 4a/b, these may be suitably protected priorto the introduction of R² and deprotected again thereafter. O-protectedderivatives 1b may be obtained from 1a according to standard literatureprocedures used for the protection of alcohols (e.g. treatment of 1awith a silylating agent such as TESCl in the presence of a suitable basesuch as DBU). The conditions for the introduction of some O-protectinggroups (e.g. O-benzylation with benzylbromide in presence of K₂CO₃) mayrequire the prior protection of the amino group (e.g. by bocylation withBoc₂O) which is deprotected again after protection of the hydroxylgroup. The removal of both O- and N-protecting groups—if desired orrequired—is carried out according to appropriate standard proceduresgenerally known to those skilled in the art (e.g. N-debocylation inpresence of TFA or N-desilylation with TBAF). Typical conditions for theintroduction and removal of protecting groups may e.g. be found in“Protective Groups in Organic Synthesis” by T. W. Greene and P. G. M.Wuts, 2^(nd) Ed., 1991, Wiley N.Y.

Derivatives with R⁴=hydroxy may be converted to derivatives withR⁴=alkoxy, aryl-lower-alkoxy- and heterocyclyl-lower-alkoxy by treatmentwith a reagent LG-R^(II), wherein R^(II)=loweralkyl, aryl-lower-alkyl orheterocyclyl-lower-alkyl in the presence of a base such as e.g. K₂CO₃.Derivatives with R⁴=hydroxy and R⁵=H may be oxidized (i.e. CR⁴R⁵ isconverted to C═O) and treated with an organometal such as e.g. Li—R⁵ orBrMg—R⁵, wherein R⁵ is lower-alkyl, aryl or heterocyclyl, to givederivatives with R⁴=hydroxyl and R⁵=lower-alkyl, aryl or heterocyclyl.If required, functional groups (e.g. present in R⁶) incompatible withconditions used for the mentioned transformations of R⁴ and R⁵, may besuitably protected and deprotected again later (according to proceduresgiven e.g. in “Protective Groups in Organic Synthesis” by T. W. Greeneand P. G. M. Wuts, 2^(nd) Ed., 1991, Wiley N.Y.).

Derivatives 1a/b-4-a/b with R¹=H may be converted to derivatives withR¹=halogen by treatment with a halogenating agent such as e.g. NCS, NBS,NIS, or N-fluoro-bis(trifluoromethylsulfonyl)amine. Derivatives1a/b-4-a/b with R¹=lower-alkyl may be obtained from derivatives withR¹=H in one step by Friedel-Crafts alkylation or in two steps byFriedel-Crafts acylation and subsequent reduction of the carbonyl group(e.g. by Wolff-Kishner- or Clemmensen-type reductions). Alternativelyderivatives with R¹=Cl, Br, or I may be subjected to ametal-halogen-exchange reaction with e.g. BuLi or EtMgBr and thentreated with an alkylating agent such as e.g. an alkyliodide. Instead ofthe alkylating agent, an aldehyde CHOalkyl may be used, leading to aderivative with R¹=1-hydroxyalkyl, that may be deoxygenated e.g. byhydrogenolysis in presence of a catalyst such as Pd/C, or by treatmentwith a reducing agent such as e.g. BH₃.Me₂S or Et₃Si—H optionally inpresence of an acid or Lewis acid such as e.g. TFA or BF₃.OEt₂ (e.g. inanalogy to Pearlstein et al., Bioorg. and Med. Chem. Lett., 2003, 13,1829-1835; Mewshaw et al., Bioorg. and Med. Chem. Lett., 2002, 12,307-310; Sakagani et al., Synlett. 1996, 163-164). If necessary,sensitive functional groups present in 1a/b-4-a/b, may be suitablyprotected prior to the preparation of derivatives with R¹=halogen orlower-alkyl and deprotected again at a later stage (e.g. according toprocedures given in “Protective Groups in Organic Synthesis” by T. W.Greene and P. G. M. Wuts, 2^(nd) Ed., 1991, Wiley N.Y.).

A large number of compounds LG-(CHR³)(CH₂)_(m)(CR⁴R⁵)_(n)R⁶ in which R¹to R⁶, L, m, n, and LG are defined as above are commercially available.If not they may be prepared from a related commercially availablestarting material such as e.g. an alcoholHO—(CHR³)—(CH₂)_(m)(CR⁴R⁵)_(n)R⁶, an esteralkylOOC—(CH₂)C—(CR⁴R⁵)_(n)R⁶, or a carboxylic acidHOOC—(CH₂)_(m)—(CR⁴R⁵)_(n)R⁶ according to standard literature procedurescommonly known to those skilled in the art. If not commerciallyavailable, halogenides of the structurehalogen-(CHR³)—(CH₂)_(m)(CR⁴R⁵)_(n)R⁶, wherein halogen=Cl or Br andeither R³=aryl or heterocyclyl or both m and n=0, may be prepared frome.g. H₂CR³—(CH₂)_(m)(CR⁴R⁵)_(n)R⁶ by treatment with NCS or NBS,respectively (e.g. Togo et al. Syn. Lett., 2003, 702-704). Oxiranes suchas 5 may be prepared by treatment of 1-bisfunctionalized ethenesC(HR³)═C(R⁵R⁶) with a commonly used epoxidizing agent such as mCPBA(e.g. Durley et al., J. Med. Chem., 2002, 45, 18, 3891-3904; Tian etal., Org. Lett., 3, 12, 2001, 1929-1932). Many of theLG-(CHR³)(CH₂)_(m)(CR⁴R⁵)_(n)R⁶ wherein R³, R⁴, R⁵=H, andR⁶=heterocyclyl may be prepared according to literature procedures (e.g.Binggeli et al. WO200292084 and WO97019311, Bouillot et al.WO2004006922; Morita et al., JP9095482; Cynkowski et al., J. Chem. Soc.Chem. Commun., 1995, 2335-2336; Kodama et al., U.S. Pat. No. 6,472,386;Faul et al., Heterocycles, 2001, 55 (4), 689-704)

After preparation of 3a/b according to the synthetic descriptions above,functional groups present in R⁶ may optionally be further derivatized.Examples for typical transformations of such functional groups aresummarized below:

Benzyloxy is typically transformed to hydroxy; hydroxy to lower-alkoxy,R^(a)—O—C(O) lower-alkoxy, and R^(a)R^(b)—NC(O)-lower-alkoxy;R^(a)—O—C(O)—, to hydroxymethyl and HO—C(O); HO—C(O) to R^(a)R^(b)NC(O);hydroxymethyl to formyl, wherein the just mentioned functional groupsmay be present alone or form part of a larger functional group andwherein R^(a) and R^(b) independently from each other are hydrogen orlower alkyl. Procedures for these transformations are found in largenumber in literature and are commonly known to those skilled in the art.

Formyl may typically be transformed to 1-hydroxyalkyl, by addition of analkylmagnesium halogenide or an alkyllithium. The formyl group may bederivatized to a 2-(loweralkyl-O—C(O))-1-hydroxy ethyl group e.g. byZn(0)-mediated addition of an α-bromoacetic acid ester(Reformatsky-reaction). If the 2-(loweralkyl-O—C(O))-1-hydroxy ethyl isformed from a formyl group directly attached to an aryl or aheterocyclyl, transformation to the alkoxycarbonylethyl-group may becarried out by deoxygenation, e.g. by hydrogenolysis in presence of acatalyst such as Pd/C, or by treatment with a reducing agent such ase.g. BH₃.Me₂S or Et₃Si—H optionally in presence of an acid or Lewis acidsuch as e.g. TFA or BF₃.OEt₂. Alternatively the transformation to thealkoxycarbonylethyl-group may be carried out by 1,2-elimination (e.g.promoted by treatment with Tf₂O in presence of a base such as DIPEA) andsubsequent hydrogenation of the alkene intermediate. Such an alkeneintermediate may also be prepared directly starting from theformyl-derivative using Wittig-, Wittig-Horner-, Wadsworth-Emmons-, orPeterson-type olefinations. Procedures for such olefinations are foundin large numbers in literature and are commonly known to those skilledin the art.

Prior to the derivatizations of the functional group on R⁶, sensitivefunctional groups 3a/b may be suitably protected (e.g. silylation of ahydroxy group) and deprotected again when desired or required (asdescribed e.g. in “Protective Groups in Organic Synthesis” by T. W.Greene and P. G. M. Wuts, 2^(nd) Ed., 1991, Wiley N.Y.).

The conversion of a compound of formula (I) into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withan inorganic acid, for example a hydrohalic acid, such as, for example,hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid etc., or with an organic acid, such as, for example,acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. The correspondingcarboxylate salts can also be prepared from the compounds of formula (I)by treatment with physiologically compatible bases.

The conversion of compounds of formula (I) into pharmaceuticallyacceptable esters can be carried out e.g. by treatment of suited aminoor hydroxy groups present in the molecules with an carboxylic acid suchas acetic acid, with a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or N,N-dicylohexylcarbodiimide (DCCl) to produce the carboxylicester or carboxylic amide.

Insofar as their preparation is not described in the examples, thecompounds of formula (I) as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth above. Starting materials are commercially available or known inthe art.

As described above, the novel compounds of the present invention havebeen found to bind to and selectively activate LXR alpha and LXR beta orcoactivate LXR alpha and LXR beta. Consequently, cholesterol absorptionis reduced, HDL cholesterol is increased, and inflammatoryatherosclerosis is reduced. They can therefore be used in the treatmentand prophylaxis of diseases which are modulated by LXR alpha and/or LXRbeta agonists. Such diseases include increased lipid and cholesterollevels, particularly low HDL-cholesterol, high LDL-cholesterol,atherosclerotic diseases, diabetes, particularly non-insulin dependentdiabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer'sdisease, sepsis, and inflammatory diseases such as colitis,pancreatitis, cholestasis/fibrosis of the liver, psoriasis and otherinflammatory diseases of the skin, and diseases that have aninflammatory component such as Alzheimer's disease orimpaired/improvable cognitive function. Moreover, the novel compounds ofthe present invention can be used for treatment and prophylaxis ofage-related and inherited (e.g. Stargardt's disease) forms of maculardegeneration.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment and/or prophylaxis of diseases which aremodulated by LXR alpha and/or LXR beta agonists, particularly astherapeutically active substances for the treatment and/or prophylaxisof increased lipid levels, increased cholesterol levels, lowHDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases,diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome,dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis,pancreatitis, cholestasis of the liver, fibrosis of the liver, maculardegeneration and/or Alzheimer's disease.

In another preferred embodiment, the invention relates to a method forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by LXR alpha and/or LXR beta agonists, particularly for thetherapeutic and/or prophylactic treatment of increased lipid levels,increased cholesterol levels, low HDL-cholesterol, high LDL-cholesterol,atherosclerotic diseases, diabetes, non-insulin dependent diabetesmellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatorydiseases, skin diseases, colitis, pancreatitis, cholestasis of theliver, fibrosis of the liver, macular degeneration and/or Alzheimer'sdisease, which method comprises administering a compound as definedabove to a human being or animal.

The invention also embraces the use of compounds as defined above forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by LXR alpha and/or LXR beta agonists, particularly for thetherapeutic and/or prophylactic treatment of increased lipid levels,increased cholesterol levels, low HDL-cholesterol, high LDL-cholesterol,atherosclerotic diseases, diabetes, non-insulin dependent diabetesmellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatorydiseases, skin diseases, colitis, pancreatitis, cholestasis of theliver, fibrosis of the liver, macular degeneration and/or Alzheimer'sdisease.

The invention also relates to the use of compounds as described abovefor the preparation of medicaments for the therapeutic and/orprophylactic treatment of diseases which are modulated by LXR alphaand/or LXR beta agonists, particularly for the therapeutic and/orprophylactic treatment of increased lipid levels, increased cholesterollevels, low HDL-cholesterol, high LDL-cholesterol, atheroscleroticdiseases, diabetes, non-insulin dependent diabetes mellitus, metabolicsyndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases,colitis, pancreatitis, cholestasis of the liver, fibrosis of the liver,macular degeneration and/or Alzheimer's disease. Such medicamentscomprise a compound as described above.

Prevention and/or treatment of increased lipid levels, increasedcholesterol levels, atherosclerotic diseases, dyslipidemia, or diabetesis the preferred indication, particularly prevention and/or treatment ofincreased lipid levels, increased cholesterol levels, atheroscleroticdiseases, or dyslipidemia, especially prevention and/or treatment ofatherosclerotic diseases or dyslipidemia.

The following tests were carried out in order to determine the activityof the compounds of the present invention. Background information on theperformed assays can be found in: Nichols J S et al. “Development of ascintillation proximity assay for peroxisome proliferator-activatedreceptor gamma ligand binding domain”, Anal Biochem. 1998, 257: 112-119.

Mammalian expression vectors were constructed to express full-lengthhuman LXR alpha and LXR beta. Bacterial expression vectors wereconstructed to produce glutathione-s-transferase (GST) fused to theligand binding domains (LBD) of human LXR alpha (aa 164 to 447) andhuman LXR beta (aa 155 to 460). To accomplish this, the portions of thesequences encoding the LBDs were amplified from full-length clones byPCR and then subcloned into the plasmid vectors. Final clones wereverified by DNA sequence analysis (Willy et al., Genes Dev. 1995,9:1033-45; Song et al., Proc Natl Acad Sci USA. 1994, 91:10809-13).

Induction, expression, and purification of GST-LBD fusion proteins wereperformed in E. coli strain BL21 (pLysS) cells by standard methods (Ref:Current Protocols in Molecular Biology, Wiley Press, edited by Ausubelet al).

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 300 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Abbreviations

Ac₂O=acetic anhydride, CH₂Cl₂=dichloromethane, ^(t)BuOH=tert-butanol,DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA=N-ethyl diisopropylamine,DMF=dimethylformamide,EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EtOAc=ethylacetate, EtOH=ethanol, Et₂O=diethylether, eq=equivalent,HCl=hydrochloric acid, HOBT=1-hydroxybenzotriazole, MeOH=methanol,NH₄Cl=ammonium chloride, NaOH=sodium hydroxide, NaOMe=sodium methoxide,NCS=N-chlorosuccinimide, RT=room temperature, TBAF=tetrabutyl ammoniumfluoride, TFAA=trifluoroacetic anhydride, TESCl=chlorotriethylsilane,THF=tetrahydrofurane.

General Remarks

All reactions were performed under argon.

Example 12-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol

1.1

A solution of 5 g (19.3 mmol) of2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 25 mL ofpyridine was treated with 2.2 mL (23.3 mmol) of Ac₂O. The mixture wasstirred at 60° C. for 2 hours and the solvent partially evaporated. Theresidue was distributed between a diluted aqueous solution of HCl andEt₂O. The combined organic phases were dried over Na₂SO₄ and evaporatedto yield 5.7 g of crudeN-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamidethat was dissolved in 100 mL of DMF, treated with 3.4 mL (22.7 mmol) ofDBU and then dropwise at 0° C. with 3.8 mL (22.7 mmol) of TESCl. Themixture was stirred at RT for 10 hours and then poured into a saturatedaqueous solution of NH₄Cl and Et₂O. The phases were separated and theaqueous one was extracted with Et₂O. The combined organic phases weredried over Na₂SO₄ and evaporated to yield 8.3 g of crudeN-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamidewhich was dissolved in 100 mL of THF and treated with 3.4 mL of a 1MBH₃*THF-solution in THF. The mixture was kept at reflux for 4 hours andthe solvent partially evaporated. After addition of a saturated aqueoussolution of NH₄Cl and Et₂O, the phases were separated and the aqueousone was extracted with Et₂O. The combined organic phases were dried overNa₂SO₄ and evaporated. Column chromatography on silica gel withn-heptane/EtOAc 9:1 yielded 7.5 g (96%) ofethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine,light yellow oil, MS: 402 (MH⁺).

1.2

To a solution of 0.5 g (1.24 mmol) ofethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-aminein 2 mL of DMF were added 0.3 mL (2.5 mmol) of benzylbromide and themixture was stirred overnight at 80° C. After distribution between a 2Maqueous solution of NaOH and Et₂O, drying of the combined organic phasesover Na₂SO₄ and evaporation, the resulting crude was dissolved in 5 mLof MeOH, treated with 1 mL of a 2M NaOMe-solution in MeOH and stirredfor 30 min. Evaporation of the solvent and column chromatography onsilica gel with n-heptane/EtOAc 95: 5 gave 0.33 g (70%) of2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow semisolid, MS: 378 (MH⁺).

Example 22-{4-[(2-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 1-chloro-2-chloromethyl-benzene was prepared2-{4-[(2-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 412 (MH⁺, 1Cl).

Example 32-{4-[(3-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 1-chloro-3-chloromethyl-benzene was prepared2-{4-[(3-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 412 (MH⁺, 1Cl).

Example 42-{4-[(4-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 1-chloro-4-chloromethyl-benzene was prepared2-{4-[(4-chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 412 (MH⁺, 1Cl).

Example 52-[4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 2-phenyl ethylbromide was prepared2-[4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 392 (MH⁺).

Example 62-[4-(benzhydryl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand bromodiphenylmethane was prepared2-[4-(benzhydryl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,pink oil, MS: 454 (MH⁺).

Example 72-{4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 4-chloromethyl-thiazole was prepared2-{4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light brown oil, MS: 385 (MH⁺).

Example 82-{4-[ethyl-(pyridin-2-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 2-bromomethyl-pyridine hydrobromide was prepared2-{4-[ethyl-(pyridin-2-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,white solid, MS: 379 (MH⁺).

Example 92-{4-[ethyl-(pyridin-3-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 3-bromomethyl-pyridine hydrochloride was prepared2-{4-[ethyl-(pyridin-3-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light brown oil, MS: 379 (MH⁺).

Example 102-{4-[ethyl-(pyridin-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 1.2, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand 4-bromomethyl-pyridine hydrochloride was prepared2-{4-[ethyl-(pyridin-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light brown oil, MS: 379 (MH⁺).

Example 112-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

11.1

A solution of 3.0 g (11.6 mmol) of2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 40 mL of CH₂Cl₂was treated with 3.0 mL (17.4 mmol) of DIPEA and dropwise at 0° with 1.8mL (12.9 mmol) of TFAA. After stirring 1 hour at RT the mixture wasdistributed between a saturated aqueous solution of NH₄Cl and Et₂O. Thecombined organic phases were dried over Na₂SO₄ and evaporated to yield4.2 g (quantitative) of crude2,2,2-trifluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide,light brown oil, MS: 356 (MH⁺).

11.2

A solution of 4.2 g (11.8 mmol) of2,2,2-trifluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamidein 30 mL of THF was treated with 24.2 mL of a 1M BH₃.THF-complexsolution in THF. The mixture was stirred for 72 hours at RT and thenrefluxed for 2 hours. After cooling to RT, the mixture was distributedbetween a saturated aqueous solution of NH₄Cl and Et₂O. The combinedorganic phases were dried over Na₂SO₄ and evaporated. Columnchromatography on silicagel with n-heptane/EtOAc 4:1 yielded 3.0 g (74%)of1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol,light brown oil, MS: 342 (MH⁺).

11.3

A solution of 100 mg (0.29 mmol) of1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-olin 0.5 mL ^(t)BuOH was treated with 0.1 mL (0.84 mmol) of benzylbromideand stirred at 100° C. for 10 hours in a sealed tube. Evaporation of thesolvent and column chromatography on silicagel with n-heptane/EtOAc 8:1yielded 10 mg (8%) of2-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,blue oil, MS: 432 (MH⁺).

Example 122-{4-[(5-chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

A solution of 100 mg (0.29 mmol) of1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol(example 11.2) in 0.5 mL ^(t)BuOH was treated with 115 mg (0.44 mmol) of5-chloro-2-chloromethyl-benzo[b]thiophene and stirred at 120° C. for 10hours in a sealed tube. Evaporation of the solvent and columnchromatography on silicagel with n-heptane/EtOAc 8:1 yielded 30 mg (19%)of2-{4-[(5-chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 520 ((M-H)⁻, 1Cl).

Example 132-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

13.1

A solution of 4 g (10 mmol) ofethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine(example 1.1) in 12 mL of acetonitrile was treated with 2.3 mL (20 mmol)of racemic phenyloxirane and 2.12 g (20 mmol) of lithiumperchlorate. Themixture was stirred overnight at 80° C. in a sealed tube. The crude wasdistributed between saturated aqueous NH₄Cl and Et₂O and the combinedorganic phases were dried over Na₂SO₄ and evaporated. Columnchromatography on silica gel with n-heptane/EtOAc 9:1 yielded 3.5 g(66%) of2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-2-phenyl-ethanol,light yellow oil, MS: 522 (MH⁺) and 0.475 g (9%) of2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-1-phenyl-ethanol,light yellow oil, MS: 522 (MH⁺).

13.2

A solution of 300 mg (0.58 mmol) of2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-1-phenyl-ethanolin 7.5 mL of THF was treated with 1.5 mL of a 1M TBAF-solution in THFand stirred at RT for 1 hour. Evaporation of the solvent and columnchromatography on silica gel with n-heptane/EtOAc 9:1 yielded 153 mg(65%) of2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,white solid, MS: 408 (MH⁺).

Example 14 (R)2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 13, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand (S) phenyloxirane was prepared (R)2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 408 (MH⁺).

Example 15 (S)2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 13, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand (R) phenyloxirane was prepared (S)2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 408 (MH⁺).

Example 16 (R)2-(4-{[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 13, fromethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amineand (S) (3-chloro-phenyl)oxirane was prepared (R)2-(4-{[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,yellow oil, MS: 440 ((M-H)⁻, 1Cl).

Example 172-[4-(benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol

A solution of 20 mg (0.05 mmol) of2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol(example 1.2) in 0.5 mL of 2-propanol was treated with 7 mg (0.05 mmol)of NCS. The mixture was stirred at 80° C. for 10 hours and the solventwas evaporated. Column chromatography on silicagel with n-heptane/EtOAc9:1 yielded 17 mg (82%) of2-[4-(benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,colorless oil, MS: 412 (MH⁺, 1Cl).

Example 182-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 17, from2-{4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol(example 7) was prepared2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light brown solid, MS: 419 (MH⁺, 1Cl).

Example 192-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 17, from2-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol(example 11.3) was prepared2-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 466 (MH⁺, 1Cl).

Example 202-{3-chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

20.1

In analogy to example 17, from2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol was prepared2-(4-amino-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, lightbrown solid, MS: 292 (M-H)⁻, 1Cl).

20.2

A solution of 1 g (3.4 mmol) of2-(4-amino-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 5 mLof pyridine was treated with 0.42 mL (4.4 mmol) of Ac₂O and stirred at70° C. for 10 hours. The solvent was evaporated, the residue dissolvedin THF, treated with a 2M aqueous solution of NaOH and stirred for 1 hat RT. After acidification of the mixture to a pH of ca. 7 by addingaqueous HCl, Et₂O and H₂O were added, the phases were separated and theaqueous one was extracted with Et₂O. The combined organic phases weredried over Na₂SO₄ and evaporated to yield 1.1 g (ca. 94%) of crudeN-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide,which was dissolved in 20 mL of DMF and treated with 0.65 mL (4.37 mmol)of DBU and then at 0° C. dropwise with 0.73 mL (4.37 mmol) of TESCl. Themixture was stirred overnight and poured into a mixture of a saturatedaqueous solution of NH₄Cl and Et₂O. The phases were separated and theaqueous one extracted with Et₂O. The combined organic phases were driedover Na₂SO₄ and evaporated to yield 1.53 g (93%) of crudeN-[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide,yellow oil, MS: 450 (MH⁺, 1Cl).

20.3

A solution of 1.54 g (3.42 mmol) of crudeN-[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamidein 20 mL of THF was treated with 6.85 mL of a 1M solution ofBH₃.THF-complex in THF. The mixture was kept at reflux for 3 hours andthe solvent evaporated. The residue was distributed between a saturatedaqueous solution of NH₄Cl and Et₂O. The combined organic phases weredried over Na₂SO₄ and the solvent was evaporated. Column chromatographyon silica gel with n-heptane/EtOAc 95:5 yielded 0.922 g (61%) of[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-amine,colorless liquid, MS: 436 (MH⁺, 1Cl).

20.4

A solution of 100 mg (0.23 mmol) of[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-aminein CH₂Cl₂ was treated with 0.08 mL (0.46 mmol) of DIPEA and 0.07 mL(0.46 mmol) of 3-phenylpropionylchloride. The mixture was stirred at RTfor 10 hours and treated with 0.4 mL of a 1 M TBAF-solution in THF.Evaporation of the solvent and column chromatography on silica gel withn-heptane/EtOAc 4:1 yielded 70 mg (67%) ofN-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide,light yellow oil, MS: 454 (MH⁺, 1Cl).

20.5

A solution of 70 mg (0.15 mmol) ofN-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamidein 3 mL of THF was treated with 1 mL of 1M BH₃.THF-complex in THF andstirred for 10 hours at 80° C. in a sealed tube. Evaporation of thesolvent and column chromatography on silica gel with CH₂Cl₂/n-heptane1:1 yielded 60 mg (91%) of2-{3-chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,colorless oil, MS: 440 (MH⁺, 1Cl).

Example 212-[3-chloro-4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol

21.1

In analogy to example 20.4, from[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-amineand phenylacetyl chloride was preparedN-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-2-phenyl-acetamide,yellow gum, MS: 440 (MH⁺, 1Cl).

21.2

In analogy to example 20.5, fromN-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-2-phenyl-acetamidewas prepared2-[3-chloro-4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,colorless oil, MS: 426 (MH⁺, 1Cl).

Example 221,1,1,3,3,3-hexafluoro-2-{4-[[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-propan-2-ol

22.1

4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole wasprepared from 3-trifluoromethyl-benzaldehyde in analogy to the proceduredescribed by Binggeli et al. (WO02/092084).

22.2

A mixture of 100 mg (0.29 mmol) of1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol(example 11.2), of 81 mg (0.29 mmol)4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole and ca 10mg of NaI in DMF was stirred for 1 week at 125° C. and then distributedbetween a saturated aqueous solution of NH₄Cl and Et₂O. Drying of thecombined organic phases over Na₂SO₄ and column chromatography on silicagel with a gradient of n-heptane/EtOAc gave 2 mg (ca. 1%) of1,1,1,3,3,3-hexafluoro-2-{4-[[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-propan-2-ol,yellow solid, MS: 581 (MH⁺).

Example 232-{4-[[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

23.1

4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole was prepared from3-chloro-benzaldehyde in analogy to the procedure described by Binggeliet al. (WO 02/092084).

23.2

In analogy to example 22.2, from1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-oland 4-chloromethyl-5-methyl-2-(3-chloro-phenyl)-oxazole was prepared2-{4-[[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,yellow solid, MS: 547 (MH⁺, 1Cl).

Example 242-(4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

24.1

A solution of 1 g (3.86 mmol) of2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 2 ml of THF and5 mL of pyridine was treated with 0.44 mL (4.63 mmol) of Ac₂O andstirred for 2 hrs at 60° C. The solvent was evaporated and the crudedistributed between a diluted aqueous solution of HCl and Et₂O. thecombined organic phases were dried over Na₂SO₄ and the solventevaporated. The residue was dissolved in 5 mL of THF, treated with 7.7mL of a 1M BH₃*THF-solution in THF and refluxed for 2 hrs. The solventwas evaporated and the residue distributed between a diluted aqueoussolution of NaOH and Et₂O. The aqueous phase was then acidified byaddition of an aqueous solution of HCl to a pH of ca. 7 and extractedwith Et₂O. The combined organic phases were dried over Na₂SO₄ and thesolvent evaporated to give 1.07 g (96%) of crude2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellowsolid, MS: 288 (MH⁺).

24.2

A solution of 100 mg (0.35 mmol) of2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and 96 mg(0.35 mmol) of4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole (example22.1) in 0.5 mL of DMF was stirred overnight at 80° C. Afterdistribution of the crude mixture between a saturated aqueous solutionof NH₄Cl and Et₂O, the combined organic phases were dried over Na₂SO₄and the solvent was evaporated. Column chromatography on silica gel withtoluene/EtOAc gave 91 mg (53%) of2-(4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,yellow solid, MS: 527 (MH⁺).

Example 252-(4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and4-chloromethyl-5-methyl-2-(3-chloro-phenyl)-oxazole (example 23.1) wasprepared2-(4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,orange solid, MS: 493 (MH⁺, 1Cl).

Example 262-(3-chloro-4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 17, from2-(4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol(example 24) was prepared2-(3-chloro-4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,yellow gum, MS: 561 (MH⁺, 1Cl).

Example 272-(3-chloro-4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

In analogy to example 17, from prepared2-(4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol(example 25) was prepared2-(3-chloro-4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow waxy solid, MS: 527 (MH⁺,2Cl).

Example 282-(4-{[2-(3-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

28.1

2-(3-benzyloxy-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared from3-benzyloxy-benzaldehyde in analogy to the procedure described byBinggeli et al. (WO 02/092084).

28.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and2-(3-benzyloxy-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared2-(4-{[2-(3-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,off-white solid, MS: 563 (M-H)⁻.

Example 292-(4-{[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol

29.1

2-(4-benzyloxy-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared from4-benzyloxy-benzaldehyde in analogy to the procedure described byBinggeli et al. (WO 02/092084).

29.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and2-(4-benzyloxy-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared2-(4-{[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow solid, MS: 563 (M-H)⁻.

Example 303-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester

30.1

3-(4-chloromethyl-5-methyl-oxazol-2-yl)-benzoic acid methyl ester wasprepared from 3-formyl-benzoic acid methyl ester in analogy to theprocedure described by Binggeli et al. (WO 02/092084).

30.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and3-(4-chloromethyl-5-methyl-oxazol-2-yl)-benzoic acid methyl ester wasprepared3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester, light yellow foam, MS: 515 (M-H)⁻.

Example 314-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester

31.1

4-(4-chloromethyl-5-methyl-oxazol-2-yl)-benzoic acid methyl ester wasprepared from 4-formyl-benzoic acid methyl ester in analogy to theprocedure described by Binggeli et al. (WO 02/092084).

31.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and4-(4-chloromethyl-5-methyl-oxazol-2-yl)-benzoic acid methyl ester wasprepared4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester, light yellow foam, MS: 515 (M-H)⁻.

Example 323-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid

A solution of 92 mg (0.18 mmol) of3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester (example 30.2) in 1 mL of THF was treated with 1 mL of1M aqueous LiOH and stirred at RT for 1 h. The mixture was acidified topH 4-5 with aqueous HCl and distributed between Et₂O and H₂O. Thecombined organic phases were dried over Na₂SO₄ and evaporated to yield79 mg (88%) of3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid, light yellow solid, MS: 503 (MH⁺).

Example 334-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid

In analogy to example 32, from4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid methyl ester (example 31.2) was prepared4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid, light yellow solid, MS: 503 (MH⁺).

Example 343-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide

A solution of 22 mg (0.04 mmol) of3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid (example 32) in 1 mL of DMF was treated with 9 mg (0.13 mmol) ofmethylamine hydrochloride and 0.03 mL (0.26 mmol) of 4-methylmorpholineand cooled to 0°. After addition of 12 mg (0.06 mmol) of EDCI and 1 mg(0.001 mmol) of HOBT the mixture was allowed to reach RT, stirred for 6hours and distributed between Et₂O and a saturated aqueous solution ofNH₄Cl. The combined organic phases were dried over Na₂SO₄ andevaporated. Column chromatography on silica gel with EtOAc gave 17 mg(75%) of3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide,colorless gum, MS: 516 (MH⁺).

Example 353-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide

In analogy to example 34, from3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid and dimethylamine hydrochloride was prepared3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide,colorless gum, MS: 530, (MH⁺).

Example 363-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide

In analogy to example 34, from3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid and ammonium chloride was prepared3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide,colorless gum, MS: 502, (MH⁺).

Example 374-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide

In analogy to example 34, from4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid (example 33) and methylamine hydrochloride was prepared4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide,white solid, MS: 516 (MH⁺).

Example 384-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide

In analogy to example 34, from4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid (example 33) and dimethylamine hydrochloride was prepared4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide,white solid, MS: 530 (MH⁺).

Example 394-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide

In analogy to example 34, from3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoicacid (example 33) and ammonium chloride was prepared4-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide,white solid, MS: 502 (MH⁺).

Example 402-{4-[(2-benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

40.1

2-Benzyl-4-chloromethyl-5-methyl-oxazole was prepared fromphenyl-acetaldehyde in analogy to the procedure described by Binggeli etal. (WO 02/092084).

40.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and2-benzyl-4-chloromethyl-5-methyl-oxazole and2-benzyl-4-chloromethyl-5-methyl-oxazole was prepared2-{4-[(2-benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,dark brown oil, MS: 473 (MH⁺).

Example 412-{4-[ethyl-(5-methyl-2-((E)-styryl)-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

41.1

4-chloromethyl-5-methyl-2-((E)-styryl)-oxazole was prepared from(E)-3-phenyl-propenal in analogy to the procedure described by Binggeliet al (WO 02/092084).

41.2

In analogy to example 24.2, from2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and4-chloromethyl-5-methyl-2-((E)-styryl-oxazole and4-chloromethyl-5-methyl-2-styryl-oxazole was prepared2-{4-[ethyl-(5-methyl-2-((E)-styryl)-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow solid, MS: 485 (MH⁺).

Example 422-{4-[ethyl-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol

A solution of 40 mg (0.08 mmol) of2-{4-[(2-benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-olin 1 mL of MeOH was treated with 20 mg of Pd/C (10%) and hydrogenated atatmospheric pressure for 20 hours. Filtration and evaporation gave 25 mg(62%) of2-{4-[ethyl-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,light yellow oil, MS: 487 (MH⁺).

Example 43

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet

Kernel: Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous60.0 mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate12.5 mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mgPolyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxice(yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example 44

Capsules containing the following ingredients can be manufactured in aconventional manner: Ingredients Per capsule Compound of formula (I)25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example 45

Injection solutions can have the following composition: Compound offormula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg Acetic Acid q.s. adpH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example 46

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner: Capsule contents Compound offormula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mgPartially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weightof capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol85% 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Ironoxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example 47

Sachets containing the following ingredients can be manufactured in aconventional manner: Compound of formula (I) 50.0 mg Lactose, finepowder 1015.0 mg  Microcryistalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcryistalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

Example 48 Radioligand Binding Assay

LXR alpha and LXR beta receptor binding were assayed in bufferconsisting of 50 mM HEPES, pH 7.4, 10 mM NaCl, 5 mM MgCl₂. For each96-well reaction, 500 ng of GST-LXRα-LBD or 700 ng of GST-LXR beta-LBDfusion proteins were bound to 80 μg or 40 μg SPA beads (PharmaciaAmersham) respectively, in a final volume of 50 μl by shaking. Theresulting slurry was incubated for 1 h at RT and centrifuged for 2 minat 1300×g. The supernatant containing unbound protein was removed, andthe semi-dry pellet containing the receptor-coated beads wasre-suspended in 50 μl of buffer. Radioligand (eg. 100,000 dpm of(N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-phenyl]-benzenesulfonamide))was added, and the reaction incubated at RT for 1 h in the presence oftest compounds, and then scintillation proximity counting was performed.All binding assays were performed in 96-well plates and the amount ofbound ligand was measured on a Packard TopCount using OptiPlates(Packard). Dose response curves were measured within a range ofconcentration from 10⁻¹⁰ M to 10⁻⁴ M.

Luciferase Transcriptional Reporter Gene Assays

Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM mediumcontaining 10% FBS at 37° C. in a 95% O2:5% CO₂ atmosphere. Cells wereseeded in 6-well plates at a density of 10⁵ Cells/well and thenbatch-transfected with either the full-length-LXRα or full-length-LXRβexpression plasmids plus a reporter plasmid expressing luceriferaseunder the control of LXR response elements. Transfection wasaccomplished with the Fugene 6 reagent (Roche Molecular Biochemicals)according to the suggested protocol. Six hours following transfection,the cells were harvested by trypsinization and seeded in 96-well platesat a density of 10⁴ cells/well. After 24 hours to allow attachment ofcells, the medium was removed and replaced with 100 μl of phenolred-free medium containing the test substances or control ligands (finalDMSO concentration: 0.1%). Following incubation of the cells for 24hours with substances, 50 μl of the supernatant was discarded and then50 μl of Luciferase Constant-Light Reagent (Roche MolecularBiochemicals) was added to lyse the cells and initiate the luciferasereaction. Luminescence, as a measure of luciferase activity, wasdetected in a Packard TopCount. Transcriptional activation in thepresence of a test substance was expressed as fold-change inluminescence compared to that of cells incubated in the absence of thesubstance. EC₅₀ values were calculated using the XLfit program (IDBusiness Solutions Ltd. UK).

The compounds according to formula (I) have an activity in at least oneof the above assays (EC50 or IC50) of 1 nM to 100 μM, preferably 1 nM to10 μM, more preferably 1 nM to 1 μM.

For example, the following compounds showed the following IC50 values inthe binding assay: LXRalpha Binding LXRbeta Binding Example IC50[μmol/l] IC50 [μmol/l] 1 0.046 0.031 18 0.017 0.0034 30 0.0027 0.0057

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of the formula (I):

wherein: R¹ is hydrogen, halogen, or lower-alkyl; R² is lower-alkyl,fluoro-lower-alkyl, cycloalkyl-lower-alkyl, or heterocyclyl-lower-alkyl;R³ is hydrogen, lower-alkyl, aryl, cycloalkyl, or heterocyclyl; R⁴ ishydrogen, hydroxy, lower-alkoxy, aryl-lower-alkoxy, orheterocyclyl-lower-alkoxy; R⁵ is hydrogen, lower-alkyl, aryl, orheterocyclyl; R⁶ is aryl or heterocyclyl; m is 0 to 3; n is 0 or 1; andpharmaceutically acceptable salts and esters thereof.
 2. The compoundaccording to claim 1, wherein R¹ is hydrogen or halogen.
 3. The compoundaccording to claim 1, wherein R¹ is hydrogen or chlorine.
 4. Thecompound according to claim 1, wherein R² is lower-alkyl orfluoro-lower-alkyl.
 5. The compound according to claim 1, wherein R² isethyl or 2,2,2-trifluoro-ethyl.
 6. The compound according to claim 1,wherein R³ is hydrogen or aryl.
 7. The compound according to claim 1,wherein R³ is hydrogen or phenyl.
 8. The compound according to claim 1,wherein R³ is hydrogen.
 9. The compound according to claim 1, wherein R⁴is hydrogen or hydroxy.
 10. The compound according to claim 1, whereinR⁵ is hydrogen.
 11. The compound according to claim 1, wherein R⁶ isphenyl, pyridinyl, thiazolyl, or benzo[b]thiophenyl, which is optionallysubstituted with halogen.
 12. The compound according to claim 1, whereinR⁶ is phenyl, chloro-phenyl, pyridinyl, thiazolyl, orchloro-benzo[b]thiophenyl.
 13. The compound according to claim 1,wherein R⁶ is phenyl.
 14. The compound according to claim 1, wherein mis 0 to
 2. 15. The compound according to claim 1, wherein m is
 0. 16.The compound according to claim 1, wherein n is
 0. 17. The compoundaccording to claim 1, selected from the group consisting of:2-[4-(Benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[(2-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[(3-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[(4-Chloro-benzyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-[4-(Ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-[4-(Benzhydryl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[ethyl-(pyridin-2-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[ethyl-(pyridin-3-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[ethyl-(pyridin-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[(5-Chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,(R)2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,(S)2-{4-[Ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,(R)2-(4-{[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-[4-(Benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,2-{3-Chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,and2-[3-Chloro-4-(ethyl-phenethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,and pharmaceutically acceptable salts and esters thereof.
 18. Thecompound according to claim 1, selected from the group consisting of:2-[4-(Benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,and2-{4-[Benzyl-(2,2,2-trifluoro-ethyl)-amino]-3-chloro-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,and pharmaceutically acceptable salts and esters thereof.
 19. A processfor the manufacture of compounds of formula (I) as defined in claim 1,comprising the step of: a) reacting a compound of formula (II):

with a compound LG-CHR³—(CH₂)_(m)—(CR⁴R⁵)_(n)—R⁶, or b) reacting acompound of formula (III):

with a compound LG-R², wherein R¹, R², R³, R⁴, R⁵, R⁶, m and n are asdefined in any of claims 1-23 and LG is a leaving group.
 20. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 and a pharmaceutically acceptablecarrier and/or adjuvant.
 21. A method for the treatment of diseaseswhich are modulated by LXR alpha and/or LXR beta agonists, comprisingthe step of administering a therapeutically effective amount of acompound according to claim 1 to a human being or animal in needthereof.